title: Role of mitofusin 2 (Mfn2) in controlling cellular proliferation.
abstract: It has been reported that Mitofusin2 (Mfn2) inhibits cell proliferation when overexpressed. We wanted to study the role of endogenous Mfn2 in cell proliferation, along with the structural features of Mfn2 that influence its mitochondrial localization and control of cell proliferation. Mfn2-knockdown clones of a B-cell lymphoma cell line BJAB exhibited an increased rate of cell proliferation. A 2-fold increase in cell proliferation was also observed in Mfn2-knockout mouse embryonic fibroblast (MEF) cells as compared with the control wild-type cells, and the proliferative advantage of the knockout MEF cells was blocked on reintroduction of the Mfn2 gene. Mfn2 exerts its antiproliferative effect by acting as an effector molecule of Ras, resulting in the inhibition of the Ras-Raf-ERK signaling pathway. Furthermore, both the N-terminal (aa 1-264) and the C-terminal (aa 265-757) fragments of Mfn2 blocked cell proliferation through distinct mechanisms: the N-terminal-mediated inhibition was due to its interaction with Raf-1, whereas the C-terminal fragment of Mfn2 inhibited cell proliferation by interacting with Ras. The inhibition of proliferation by the N-terminal fragment was independent of its mitochondrial localization. Collectively, our data provide new insights regarding the role of Mfn2 in controlling cellular proliferation.
authors.affiliation: 2Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Biomedical Research Center, 251 Bayview Blvd., Baltimore, MD 21224, USA. P.G., ghoshp@grc.nia.nih.gov.
authors.forename: Kuang-Hueih
authors.initials: KH
authors.lastname: Chen
authors.forename: Asish
authors.initials: A
authors.lastname: Dasgupta
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.forename: Fred E
authors.initials: FE
authors.lastname: Indig
authors.forename: Paritosh
authors.initials: P
authors.lastname: Ghosh
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: ERK; HSG; Raf; Ras